The proposed research is a multidisciplinary, multicenter, collaborative study to investigate the clinical, cardiac, and genetic aspects of the Long QT Syndrome (LQTS) - a heritable disorder with delayed repolarization, episodic malignant arrhythmias with syncope and sudden death, and recently demonstrated gene linkage in a large pedigree. The five-year research plan consists of: 1) investigation of genetic heterogeneity in LQTS by testing for Harvey-ras-1 gene linkage in the existing well-characterized LQTS families with evidence of a major gene by segregation analysis; in LQTS families that do not show Harvey-ras- 1 linkage, a search for other closely linked genetic markers will be initiated; 2) exploration by segregation analysis of the likelihood that a second gene coexists with the Harvey-ras-1 gene to explain a more malignant disease process in some LQTS families than in others; 3) establishment of normal standards for 6 quantitative repolarization parameters on a healthy population (n=4,000) using digitized ECG recordings, and biomedical and statistical techniques with adjustment for age, gender, race, and heart rate; 4) continuation of existing LQTS registry with ongoing enrollment of new families and follow-up of new and existing LQTS pedigrees (n=370 families) in order to provide a central repository for this disorder, especially as it relates to the natural history of this disorder and ongoing genetic analyses; 5) investigation of the static (12-lead ECG) and dynamic (24-hour Holter ECG) aspects of ventricular repolarization in LQTS families showing Harvey-ras gene linkage to upgrade the ECG categorization of delayed repolarization using the Harvey-ras- 1 marker as the gold standard to identify affected and unaffected individuals; and 6) continuation of the prospective longitudinal follow-up study of LQTS families to better understand the long-term clinical course of this disorder; time-dependent survivorship analyses will be performed to evaluate the effects of various clinical features, repolarization severity (QTc length), Harvey-ras-I gene linkage, and therapeutic efficacy with antiadrenergic therapy (if data permits) on outcome event rates (syncope and sudden death) in the LQTS probands. This integrated research program offers a substantial prospect of: 1) improving the presymptomatic diagnosis and treatment of LQTS; and 2) providing a fundamental under-standing of the molecular basis of repolarization-related cardiac arrhythmias.